Chronic pancreatitis is a serious and painful disorder of exocrine pancreas with no effective therapeutic measures. After biliary duct disease, chronic alcohol abuse is the second major cause of chronic pancreatitis. The economic and social impact of pancreatitis is devastating due to irreversible nature of the disease and related high mortality and co-morbidities including maldigestion, diabetes, and pancreatic cancer. Autodigestion of pancreatic tissue due to the activation of digestive zymogens in the exocrine pancreas is known to cause pancreatitis. However, metabolic basis of alcoholic pancreatitis is relatively obscure. Role of ethanol metabolites, acetaldehyde (oxidative metabolite) and fatty acid ethyl esters (FAEEs, nonoxidative lipid metabolites) in the initiation and progression of pancreatitis" is one of the focus areas of NIAAA sponsored research programs (PA-09-164). In preliminary dose-dependent studies, we found that pancreatic injury along with substantial increases in blood alcohol concentration (BAC) and pancreatic lipids, fatty acid ethyl esters (FAEEs, nonoxidative lipid metabolites of ethanol) and endoplasmic reticulum (ER) stress in hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) vs. normal ADH (ADH+) deer mice fed 3.5% ethanol (an optimal tolerable dose) for 2 months (subchronic exposure). However, the levels of blood acetaldehyde were found to be similar in both strains of deer mice fed ethanol. Based upon our preliminary data in deer mouse model and the cytotoxic effects of FAEEs reported by us and others in pancreatic acinar cells, we hypothesize that chronic ethanol exposure under hepatic ADH inhibition induces ER stress due to endogenous formation of nonoxidative lipid metabolites of ethanol in the exocrine pancreas resulting in initiation and progression of alcoholic pancreatitis. In Aim 1, we will characterize progression of lipid metabolomic changes and increases in FAEEs in the pancreas of ADH- deer mice after chronic ethanol exposure for 3 and 6 months. We will assess fatty changes and endogenous levels of FAEEs in the pancreas by proton and/or 31phosphorus nuclear magnetic resonance spectroscopy. In Aim 2, we will examine the progression of pancreatic injury, ER stress and proinflammatory responses in ethanol fed ADH- deer mice from Aim 1. Pancreatic injury will be evaluated by morphometry and injury markers, pancreatic ER stress by measuring the over expression of glucose regulated protein 78 and related cell death pathways, and inflammatory responses by proinflammatory transcription factors and cytokines in the pancreas and/or plasma. Our plasma data on markers of injury and changes in lipid metabolome can be utilized for early detection of developmental pancreatitis. The combined results of both aims should determine role/contribution of FAEEs in initiation and progression of alcoholic pancreatitis and identify its biomarkers. This information will be utilized to develop a translational research project for the early detection and intervention of alcoholic pancreatitis. Our strong existing interdisciplinary team of investigators and preliminary data in deer mouse model make us uniquely qualified to pursue this project. PUBLIC HEALTH RELEVANCE: NARRATIVE: Alcoholic pancreatitis is a devastating disease and painful disorder of exocrine pancreas often causes high mortality and associated with co-morbidities including maldigestion, diabetes, and pancreatic cancer. In this project, we will establish metabolic basis of alcoholic pancreatitis, and identify early markers of ethanol-induced pancreatic injury for a translational research project for early detection and prevention of alcoholic pancreatitis.